Alzheimer’s disease is characterized by a highly heterogeneous and complex pathology influenced by a multitude of factors, including genotype, environment, cognitive reserve, and demographic variables. The heterogeneity in Alzheimer’s presentation is driven by these diverse influences, making the disease difficult to predict, diagnose, and treat uniformly.
A promising therapeutic approach being investigated by Anavex Life Sciences, a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders. The approach involves the activation of upstream, endogenous pathways for clearing protein aggregates.
Genetic and Demographic Factors
Genetic factors play a crucial role in the variability seen in Alzheimer’s. The presence of the APOE ε4 allele, for instance, significantly increases the risk and alters the course of the disease. However, not all individuals with this genetic marker develop AD, indicating that other genetic and nongenetic factors also contribute. Environmental influences, such as exposure to toxins and lifestyle choices, further modulate the disease’s onset and progression. Demographic characteristics, including age, sex, and ethnicity, also contribute to the disease’s complexity. Women, for example, are disproportionately affected by AD, and age remains the most significant risk factor, with prevalence doubling every five years past the age of 65.
Multiple biological pathways are implicated in the pathogenesis of AD. Central to this are the defective clearance mechanisms of amyloid-beta and tau proteins, leading to their accumulation and the formation of plaques and neurofibrillary tangles, respectively. These protein aggregates disrupt neuronal function and trigger a cascade of neurodegenerative processes. However, AD isn’t solely driven by Aβ and tau pathology. Other pathways, including neuroinflammation, oxidative stress, and mitochondrial dysfunction, also play critical roles.
Anavex’s strategy aims to enhance the brain’s natural mechanisms for degrading and removing toxic proteins. By boosting these intrinsic processes, it may be possible to reduce the burden of Aβ and tau, thereby slowing disease progression and preserving cognitive function.
The Role of Sigma-1 Receptor Agonists
The dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of neurodegenerative diseases such as Alzheimer’s. As such, the modulation of autophagy as the protein clearance process has become a chief pharmacological target.
Sigma-1 receptor activation is recognized as one potential approach for the prevention and therapy of neurodegeneration due to the role of Sig-1R receptors in learning and memory and other factors. For this reason, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration.
Autophagy, the cellular process of degrading and recycling cellular components, holds potential as an upstream compensatory therapeutic intervention in Alzheimer’s disease. In AD, impaired autophagy leads to the accumulation of misfolded proteins and damaged organelles, contributing to neuronal dysfunction and death. Enhancing autophagy can clear amyloid-beta plaques and tau tangles, hallmark features of AD pathology. Therapeutic strategies targeting autophagy, such as mTOR inhibitors and autophagy enhancers, aim to restore cellular homeostasis and reduce neurodegeneration. By addressing these underlying cellular dysfunctions early in the disease process, autophagy-based interventions could slow or prevent the progression of Alzheimer’s disease.
Anavex 2-73, also known as blarcamesine, a therapeutic developed by Anavex, is already in clinical investigation for the treatment of Alzheimer’s disease. The novel activities of this compound on autophagy and proteostasis currently being studied may have consequences for the use and further development of Sig-1R as a drug target in the future.
Proof of Concept Derived From Preclinical and Clinical Studies
Recent data has confirmed the pharmacological potentiality of Anavex 2-73. This compound, while presenting a micromolar order of affinity for its pharmacological targets, showed a similar active dose as compared with similar compounds, both presenting nanomolar affinities for the muscarinic or σ1 receptor, limiting the adverse effects usually observed with pure muscarinic receptor ligands. This clearly suggests that both receptors target GSK-3β activity and that inhibiting this kinase efficiently decreased Tau hyperphosphorylation and Aβ accumulation in the AD model.
Blarcamesine proof of concept from previous preclinical studies in Alzheimer’s disease demonstrated that:
— Treatment with blarcamesine (Anavex 2-73) inhibited the amyloid peptide-induced generation of Aβ1-42.
— Tau hyperphosphorylation (S202, T205 and S212, T214) was also inhibited in a dose-dependent manner.
Currently, over 120,000 Alzheimer’s patients succumb to the disease annually in the U.S., with an estimated 6.7 million Americans age 65 and older living with Alzheimer’s dementia today. Globally, the disease affects more than 50 million individuals. Research into the endogenous pathways currently being explored by Anavex Life Sciences could pave the way for innovative treatments that address the multifaceted nature of AD, offering hope for more effective management of this devastating disease.